Teratogenic effects of lithium in mice

Abstract

The question of the teratogenicity of lithium carbonate was tested in two inbred strains of mice that are susceptible to teratogens. Strains 129 and A/J mice were treated with varying dosages of lithium carbonate on day 8, 9, or 10, and strain A/J mice were sequentially treated on days 11, 12, and 13 of gestation. Another group of mice of strain 129 were given lithium carbonate in drinking water throughout pregnancy. Levels of lithium were determined in mouse serum (and in brain) of mothers and their offspring with the purpose of comparing equivalent values in mice and in man. A baseline dosage of 0.8 mg of lithium carbonate was chosen, since this dose produced a serum lithium level of 0.8 meq/L, which is comparable to values of patients treated for manic-depressive illness. This baseline dosage or 2 and 4 times this amount did not prove teratogenic in strain 129 mice. However, 5.0 mg (200 mg/kg), which is one-half the LD50 value, caused 41% malformations. The baseline dosage did not cause malformations in strain A/J when given on day 11, 12, or 13 of gestation. Lithium carbonate given in the drinking water to strain 129 mice throughout pregnancy at a concentration that produces serum levels in mice consistent with human values was deleterious. The data suggest that whole or part of total litters were eliminated. The few survivors were apparently normal. Our results suggest that 6 times the therapeutic serum lithium level in humans is teratogenic in mice, as tested by acute experiments. Chronic treatment with a quantity of lithium that produces a serum level equivalent to that of human values is toxic to whole or part of the litters of mice.

Folate rescues lithium-, homocysteine- and Wnt3A-induced vertebrate cardiac anomalies

“…Using rodent or avian models, we targeted the embryo during the primitive-streak stage. Previous studies have exposed the embryo to Li or HCy, but only after a tubular cardiac structure was already present at E8.0, or later (Nelson et al, 1955;Rosenquist et al, 1996;Smithberg and Dixit, 1982). This communication compares our HCy exposure studies during gastrulation with the cardiac defects induced by Li and analyzes the common FA rescue of the defects.…”

Testing the vulnerability of the phylotypic stage: On modularity and evolutionary conservation

“…We found that not only serious abnormalities such as exencephaly significantly were over-represented in dead fetuses (Shenefelt, 1972) but also minor anomalies with only a local effect on the fetus such as a cleft lip ( Fig. 2; Walker and Crain, 1959;Smithberg and Dixit, 1982;Juriloff and Harris, 1985;Nakane and Kameyama, 1983) and a short tail (Dostal and Jelinek, 1979). The presence of an anomaly with a small local effect cannot increase mortality by itself (see control experiment in Fig.…”

Severe toxicity and cyclooxygenase (COX)-2 mRNA increase by lithium in the neonatal mouse kidney

“…These differences could be attributable, in part, to a difference in kinetics of LiCl and TCDD. The elimination half-life of LiCl and TCDD are about 4 hr (Smithberg and Dixit, 1982) and 10-24 d (Birnbaum, 1986), respectively. We administered LiCl daily to keep its effects, which should have resulted in the oscillation of serum lithium level with a high level immediately after injection and a low level before the next injection.…”

“…In conclusion, lithium is contraindicated for use in the pregnant and lactating women because teratogenicity, such as fused ribs and defective vertebra, was reported in mouse (Smithberg and Dixit, 1982) and rat (Marathe and Thomas, 1986), and is suspected in humans from retrospective studies (Yacobi and Ornoy, 2008). However, the prospective studies of lithium treated women in pregnanand Ornoy, 2008).…”